Suppression of measles virus vaccination by maternal antibodies

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DESCRIPTION (provided by applicant): Measles virus (MV) infection causes 800,000 deaths per year. Infants cannot be protected by early immunization due to the fact that maternal antibodies (even at non-protective titers) inhibit vaccination. Although this phenomenon is seen with many vaccines of importance in human and veterinary medicine, so far the underlying mechanism is unknown. Our goal is to elucidate the regulatory mechanisms controlling inhibition of vaccination as a necessary requisite to improve immunization strategies. Our specific hypothesis is that the inhibition of the B cell response by virus-antibody complexes through the constant region (Fc) of IgG is responsible for inhibition of seroconversion and that co-immunization with IgM specific for MV can overcome this inhibition. This is supported by our preliminary data demonstrating that monoclonal MV specific IgG can inhibit vaccination and that monoclonal MV specific IgM induces neutralizing antibodies after vaccination in the presence of maternal antibodies. To analyse inhibition of vaccination in vivo we use inbred cotton rats (Sigmodon hispidus) because they are the only rodents in which MV replicates in the respiratory tract after intranasal infection. Maternal antibodies are simulated by passive transfer of MV specific serum or monoclonal antibodies. This allows us to distinguish between passively transferred human/mouse and actively induced cotton rat antibodies by ELISA. The decay of heterologous antibody is faster than homologous antibody and the amount of antibody at the time of immunization can be quantified. In this animal model we will address the following specific aims: 1. Define the mechanism of inhibition of B cell responses by IgG through FcyRIIB. We will define the role of the constant region of IgG for inhibition and the role antibody density plays in inhibition of B cell responses. 2. Define the mechanism of stimulation of B cell responses by IgM. We will define the role of binding of IgM to complement receptor 2 and the role number and density of antibody plays in stimulation of B cell responses. The effect of co-application of heterologous (mouse) IgM in relation to homologous (cotton rat) IgM will be tested in neonates with maternal antibodies.